ABSTRACT Chronic obstructive pulmonary disease (COPD) is an HIV-associated lung disease and a leading cause of morbidity and mortality, and its clinical significance is increasing as the HIV+ population ages worldwide. Despite this, our understanding of the mechanisms underlying HIV+ COPD is limited but both HIV-related and COPD- specific mechanisms are hypothesized. An improved understanding is critical for developing new therapies to treat or prevent this growing problem. This study builds upon a novel, established multinational (US and Uganda) cohort of HIV+ persons. The study measured selected markers of immune activation, inflammation, lung injury, and cellular aging in both blood and lung specimens. The study also performed lung function testing and examined the associations between the selected markers and lung function. Our data show that different markers are associated with different lung function abnormalities, suggesting that these lung function abnormalities may be due to different underlying mechanisms. Interestingly, cytomegalovirus (CMV), which is a chronic viral infection common in HIV+ persons, has been associated with the three markers most strongly associated with one of the lung function abnormalities. These data lead to the following specific aims: Aims 1 and 2: To test the hypothesis that persistent abnormalities in selected markers of immune activation, inflammation, lung injury, and cellular aging measured in the blood are associated with subsequent changes (declines) in lung function and that the specific markers associated with each lung function abnormality will be different. The longitudinal study design will strengthen the causal inferences from our earlier work and will set the foundation for future trials of therapeutic interventions, including the potential for personalized medicine with potentially novel and/or different therapies for different biomarker and/or different lung function abnormalities. Aim 3. In a cross-sectional subset of HIV+ participants selected to undergo bronchoscopy and collect lung specimens, to test the hypothesis that abnormalities in the same markers but now measured in lung specimens are associated with abnormal lung function and test the hypothesis that asymptomatic CMV co-infection is also associated with lung function abnormalities and is mediated by these markers. This aim will determine whether CMV co-infection is involved in lung function abnormalities and potentially set the stage for trials of anti-CMV therapy in HIV+ COPD. To address these aims, we will conduct a longitudinal study of 400 HIV+ subjects (200 in the US and 200 in Uganda) and collect and bank blood specimens at the same time as lung function testing. We will also perform bronchoscopy in a subset of 80 subjects (40 in the US and 40 in Uganda) and collect and bank lung specimens and specimens to assess for CMV co-infection at the same time as lung function testing. The banked specimens will allow for efficient testing of new and novel markers in the future. Our long-term objective is to improve our mechanistic understanding of lung function abnormalities seen in persons with HIV that would lead to a future study that tests new treatments for this important and growing clinical problem.